Several ecteinascidins (or Et's) have been reported previously in the patent and scientific literature. See, for example, Holt, T. G. Ph.D. Thesis, (University of Illinois, Urbana), (1986); Chem. Abstr., 106, 193149u; (1987); Diss. Abstr. Inc. B, 47, 3771-3772 (1987); Rinehart et al., U.S. patent application Ser. No. 872,189, filed Jun. 9, 1986; PCT Intl. Appln. WO87 07,610, filed Dec. 17, 1987; Chem. Abstr., 109, 811j. (1988); Rinehart et al., in Topics in Pharmaceutical Sciences 1989, eds. Breimer et al., (Amsterdam Medical Press B. V., Noordwijk, The Netherlands), pp. 613-626 (1989); Rinehart et al., in Biological Mass Spectrometry, pp. 233-258, eds. Burlingame et al., (Elsevier, Amsterdam (1990)), (1990); Rinehart et al., J. Nat. Prod., 53, 771-792, (1990); Rinehart et al., Pure Appl. Chem., 62, 1277-1280 (1990); Rinehart et al., J. Org. Chem., 55, 4512-4515, (1990); see also, Sakai et al., Proc. Natl. Acad. Sci., 89, 11456-460, dated Dec. 1, 1992.
Other ecteinascidins (Et's), e.g., Et's 729, Compound 1, 743, Compound 2, (see structure infra) and their derivatives, were isolated from the Caribbean tunicate Ecteinascidia turbinata, and two Et's (729 and 743) were later described by others. (See for example, Wright et al., J. Org. Chem., 55, 4508-4512 (1990)).
Et's 729 and 743, Compounds 1 and 2, are currently undergoing preclinical evaluation from the National Cancer Institute on the basis of exceedingly potent activity in vivo against a variety of tumor models in mice (cf. below). The major component, Et 743, Compound 2, and the others were assigned tris(tetrahydroisoquinoline) structures by correlation NMR techniques, as well as by FABMS and tandem MS (FABMS/MS).
However, the NMR data observed, including NOE's, did not allow unambiguous stereochemical assignment at C-1' in the C-subunit or at C-4 in the B-subunit and the minute quantities isolated limited further chemical investigation of these Compounds. Recently additional Et's, Compounds 5 through 7, as well as Compounds 1 and 2 have been isolated and characterized. Recrystallization of Compounds 5 and 4, a 21-O-methyl derivative of Compound 3, gave single crystals which allowed X-ray analyses of these remarkable compounds (see, Sakai, PNAS 1992, supra).